Olaya Juan C, Heusner Carrie L, Matsumoto Mitsuyuki, Shannon Weickert Cynthia, Karl Tim
Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW 2031, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
Astellas Research Institute of America LLC, Skokie, IL, USA.
Behav Brain Res. 2018 Nov 1;353:227-235. doi: 10.1016/j.bbr.2018.03.026. Epub 2018 Mar 17.
Elevated levels of the type III (III) isoforms of neuregulin 1 (NRG1) have been observed in the brains of schizophrenia patients that carry NRG1 Hap risk alleles, which is thought to contribute to the aetiology of the disease. We generated transgenic mice with forebrain driven Nrg1 III overexpression (Nrg1 III tg) and previously found that male heterozygous Nrg1 type III tg mice exhibit several schizophrenia-relevant behaviours including social and cognitive deficits as well as impaired sensorimotor gating. A number of mouse models for other Nrg1 isoform types exhibit sex-specific phenotypes yet sex-specific effects of Nrg1 III overexpression had not been evaluated. Thus, in this study we tested female Nrg1 III transgenic mice using a comprehensive behavioural phenotyping battery relevant to positive, negative and cognitive symptoms of schizophrenia. Firstly, forebrain Nrg1 III mRNA overexpression was confirmed in female transgenic mice using by qPCR. In the open field test, female Nrg1 III mice exhibited a blunted response to an acute challenge with the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. Female Nrg1 III tg mice also exhibited moderately impaired short-term memory. Other behavioural domains including sensory abilities, motor functions, baseline locomotion, anxiety, sociability, social recognition memory, fear conditioning and prepulse inhibition were unperturbed in Nrg1 III tg females. Together these results illustrate that overexpressing forebrain Nrg1 III in female mice modifies the locomotive response to NMDA receptor antagonism without causing severe alterations to a number of other schizophrenia-related behavioural domains. The data suggest that behavioural effects of Nrg1 III overexpression may be sex-dependent.
在携带神经调节蛋白1（NRG1）单倍型风险等位基因的精神分裂症患者大脑中，已观察到神经调节蛋白1（NRG1）的III型（III）亚型水平升高，这被认为与该疾病的病因有关。我们构建了前脑驱动的Nrg1 III过表达转基因小鼠（Nrg1 III tg），此前发现雄性杂合Nrg1 III型tg小鼠表现出一些与精神分裂症相关的行为，包括社交和认知缺陷以及感觉运动门控受损。许多其他Nrg1亚型的小鼠模型表现出性别特异性表型，但尚未评估Nrg1 III过表达的性别特异性影响。因此，在本研究中，我们使用与精神分裂症的阳性、阴性和认知症状相关的综合行为表型分析方法对雌性Nrg1 III转基因小鼠进行了测试。首先，通过qPCR证实雌性转基因小鼠前脑Nrg1 III mRNA过表达。在旷场试验中，雌性Nrg1 III小鼠对N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801的急性挑战反应迟钝。雌性Nrg1 III tg小鼠还表现出短期记忆中度受损。其他行为领域，包括感觉能力、运动功能、基线运动、焦虑、社交能力、社会识别记忆、恐惧条件反射和前脉冲抑制，在Nrg1 III tg雌性小鼠中未受干扰。这些结果共同表明，在雌性小鼠中过表达前脑Nrg1 III会改变对NMDA受体拮抗剂的运动反应，而不会对许多其他与精神分裂症相关的行为领域造成严重改变。数据表明，Nrg1 III过表达的行为效应可能具有性别依赖性。
